This invention relates to transdermal drug delivery systems utilizing one-way membranes which permit a drug penetration enhancing solvent contained in an overlying reservoir to flow from the solvent reservoir into a drug containing compartment adjacent thereto but prevents significant back flow of water or drug into the solvent reservoir. More particularly, this invention relates to transdermal drug delivery systems utilizing novel one-way membranes which enable a lower alkanol solvent to flow from a solvent reservoir to a drug compartment at high solvent flux to assure a constant delivery of drug and penetration enhancing alkanol solvent to the skin of a patient.
The aim of a transdermal drug delivery system is to provide a continuous and relatively constant infusion of a medicinal agent across the skin for a prolonged period of time. There are numerous transdermal drug delivery systems taught in the art. Typical of the prior art relating to such systems are Chandrasekaran, et al., U.S. Pat. No. 4,201,211 (1980) "Therapeutic for Administering Clonidine Transdermally"; Campbell, et al. U.S. Pat. No. 4,379,454 (1983) "Dosage for Coadministering Drug and Percutaneous Absorption Enhancer"; Shaw, et al, U.S. Pat. No. 4,486,193 (1984) "Method for Treating Ischemic Conditions by Administering Drug by Two Routes"; Gale, et al, U.S. Pat. No. 4,588,580 (1986) "Transdermal Administration of Fentanyl and Device Therefor" and Gale et al., U.S. Pat. No. 4,681,584 (1987) "Transdermal Delivery System for Delivering Nitroglycerin at High Transdermal Fluxes".
The permeation of many drugs is limited by the skin. The resistance of the skin to being penetrated by medicinal agents is well documented. As compared to mucosal tissues, the stratum corneum is compact and highly keratinized and quite impermeable. Such impermeability of the skin is highly essential to the well being of a living organism in that it serves as a barrier to the ingress of pathogens and toxic materials, and the egress of physiologic fluids.
The impermeability of medicinal agents through the skin is due to the nature of the very thin stratum corneum layer which is only 10-15 cells, i.e. about 10 microns thick. This layer is formed naturally by cells migrating toward the skin surface from the basal layer. Cells slowly move from the basal layer to the surface where they are sloughed off. As the progress toward the surface they become progressively more dehydrated and keratinized.
Because of the advantages of dermal application of drugs or other medicinal agents, various penetration enhancers have been sought. A penetration enhancer is one or more compounds which alter the skin as a barrier to increase the flux of a desired drug across the skin layer. One class of enhancers is solvents. The co-delivery of drug and solvent, such as lower alkanols, to increase skin transport is a major concern in the design of effective transdermal delivery systems. See for example, Durrheim, et al., J. Pharm. Sci., 69, (1980) 781-786; Ghanem, et al., J. Controlled Release, 6 (1987) 75-83 and Barry, J, Controlled Release, 6, (1987) 85-97. It is known that an ethanol permeation rate of 800 ug/cm.sup.2 /hr can aid in the permeation of some drugs across the skin barrier. This use of a lower alkanol such as ethanol, propanol or isopropanol in a transdermal delivery device is twofold. First, alkanol acts as a permeation enhancer. Second, it also aids in solubilizing the drugs.
In conventional membrane-based transdermal delivery systems the solvent and the drum, at saturation, reside in a single reservoir from which the delivery of both components to the skin is controlled by the outer membrane separating the system from the skin. This design has certain inherent deficiencies. Hydration of the skin affects drug transport. Consequently, the activities of solvent, such as an alkanol, and water must be optimized at the skin surface. This multicomponent enhancer deliver problem is particularly difficult if the drug and solvent flux are controlled by the same membrane. Since the reservoir does not usually contain water, the hydration is caused by water being delivered to the skin surface from beneath the stratum corneum. In any delivery system containing an alkanol solvent reservoir, whether separate or combined with the drug compartment, if water from beneath the skin and drug, from the drug compartment, can permeate into the alkanol solvent reservoir there will be a mixing of alkanol, water and drug in the solvent with the resultant decrease of drug concentration in the drug donor chamber. This obviously causes a decrease in the drug concentration adjacent the skin and lowers the drug flux. Also, in many systems the permeation rate of the solvent across the skin is often higher than that of the drug. In this situation, the transdermal delivery may fail to sustain drug release due to the rapid depletion of solvent from the system.
Another problem which may arise is the cost. When the drug is expensive and highly soluble in the enhancing solvent, the necessity of incorporating the drug into the reservoir can make the cost of the transdermal system impractical.
It would therefore be desirable to have a delivery system with permitted the permeation of alkanol from a separate solvent reservoir but prevented the back permeation of water and/or drug from a drug donor chamber into a solvent reservoir. Such as delivery system would require the presence of a membrane barrier which would allow solvent diffusion while preventing back diffusion of water and solute. This membrane could appropriately be categorized as a one-way diffusion membrane.
Existing polymeric materials are not suitable for such purposes. For example, a 2 mil low density polyethylene (PE) membrane will transmit ethanol at only 23 ug/cm.sup.2 /hr, but has an ethanol-water selectivity ratio of 19, e.g., the ratio of their respective fluxes. For a suitable one-way membrane the selectivity ratio should be high. A higher ethanol flux may be obtained by incorporating vinyl acetate into the PE. A 2 mil PE membrane containing 9% vinyl acetate has an ethanol flux of about 400 ug/cm.sup.2 /hr but the selectivity ratio decreased to about 8. If the vinyl acetate content is increased to about 40%, the ethanol flux increases to 7.5 mg/cm.sup.2 /hr, but the selectivity ratio drops to 2.3.
Certain silastic polymers (silicone rubbers) are significantly better. A typical silastic polymer 2 mil membrane has an ethanol flux of about 450 ug/cm.sup.2 /hr and an ethanol to water selectivity ratio greater than 50.